The Association between Elevated Levels of Peripheral Serotonin and Its Metabolite – 5-Hydroxyindoleacetic Acid and Bone Strength and Metabolism in Growing Rats with Mild Experimental Chronic Kidney Disease

Pawlak, Dariusz; Oksztulska-Kolanek, Ewa; Znorko, Beata; Domaniewski, Tomasz; Rogalska, Joanna; Roszczenko, Alicja; Brzóska, Małgorzata M.; Pryczynicz, Anna; Kemonä, A; Pawlak, Krystyna

doi:10.1371/journal.pone.0163526

Cited by 28 publications

(28 citation statements)

References 57 publications

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“…Of these, three-point bending is a simple, reproducible test, making it the preferred method of mechanical testing in small animal fracture models [ 4 , 8 , 24 ]. Usually, the three-point bending setup implies bearing bars with a fixed distance of 14 to 18 mm and a loading intender centred in between (regardless of individual bone length); force is applied perpendicularly to the bone with a constant speed of 2 to 5 mm/min [ 13 , 25 ]. So even a simple procedure like three-point bending has experienced multiple modifications precluding comparability and integrity of data.…”

Section: Discussionmentioning

confidence: 99%

Improving results in rat fracture models: enhancing the efficacy of biomechanical testing by a modification of the experimental setup

Prodinger

Bürklein²,

Foehr

et al. 2018

BMC Musculoskelet Disord

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BackgroundAnimal fracture models, primarily performed in rats, are crucial to investigate normal and pathological bone healing. However, results of biomechanical testing representing a major outcome measure show high standard deviations often precluding statistical significance. Therefore, the aim of our study was a systematical examination of biomechanical characteristics of rat femurs during three-point bending. Furthermore, we tried to reduce variation of results by individually adapting the span of bearing and loading areas to the bone’s length.MethodsWe examined 40 paired femurs of male Wistar-rats by DXA (BMD and BMC of the whole femur) and pQCT-scans at the levels of bearing and loading areas of the subsequent biomechanical three-point bending test. Individual adjustment of bearing and loading bars was done respecting the length of each specimen. Subgroups of light (< 400 g, n = 22) and heavy (> 400 g, n = 18) animals were formed and analysed separately. We furthermore compared the results of the individualised bending-setting to 20 femurs tested with a fix span of 15 mm.ResultsFemurs showed a length range of 34 to 46 mm. The failure loads ranged from 116 to 251 N (mean 175.4 ± 45.2 N; heavy animals mean 221 ± 18.9 N; light animals mean 138.1 ± 16.4 N) and stiffness ranged from 185 N/mm to 426 N/mm (mean 315.6 ± 63 N/mm; heavy animals mean 358.1 ± 34.64 N/mm; light animals mean 280.8 ± 59.85 N/mm). The correlation of densitometric techniques and failure loads was high (DXA R2 = 0.89 and pQCT R2 = 0.88). In comparison to femurs tested with a fix span, individual adaptation of biomechanical testing homogenized our data significantly. Most notably, the standard deviation of failure loads (221 ± 18.95 N individualized setting vs. 205.5 ± 30.36 N fixed) and stiffness (358.1 ± 34.64 N/mm individualized setting vs. 498.5 ± 104.8 N/mm fixed) was reduced by at least one third.ConclusionsTotal variation observed in any trait reflects biological and methodological variation. Precision of the method hence affects the statistical power of the study. By simply adapting the setting of the biomechanical testing, interindividual variation could be reduced, which improves the precision of the method significantly.Electronic supplementary materialThe online version of this article (10.1186/s12891-018-2155-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Improving results in rat fracture models: enhancing the efficacy of biomechanical testing by a modification of the experimental setup

Prodinger

Bürklein²,

Foehr

et al. 2018

BMC Musculoskelet Disord

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“…Recently, we demonstrated the association between peripheral serotonin metabolism and bone biomechanical properties in growing 5/6 Nx rats. The impaired kidney function in these animals affected the peripheral serotonin metabolism, which was associated with the pathological changes in bone structure (Pawlak et al, 2016 ). What is worth noting, only 1% of tryptophan is used for serotonin synthesis, but as much as 95% is metabolized via the kynurenine pathway (Stone, 1993 ).…”

Section: Discussionmentioning

confidence: 99%

“…Despite increasingly sophisticated diagnostic techniques for CKD-MBD, the pathophysiology of this disorder raises many doubts due to its complexity (Hruska et al, 2017 ). Our recent study indicates that the elevated concentrations of peripheral serotonin, a monoamine synthesized from tryptophan, correlates inversely with bone stiffness in growing rats with experimental CKD (Pawlak et al, 2016 ). In bone biology, peripherally synthesized serotonin inhibits bone formation.…”

Section: Introductionmentioning

confidence: 98%

Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

et al. 2017

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The diagnosis and treatment of bone disorders in patients with chronic kidney disease (CKD) represent a clinical challenge. CKD leads to mineral and bone complications starting early in the course of renal failure. Recently, we have observed the positive relationship between intensified central kynurenine turnover and bone strength in rats with subtotal 5/6 nephrectomy (5/6 Nx)-induced CKD. The aim of the present study was to determine the association between peripheral kynurenine pathway metabolites and bone strength in rats with 5/6 Nx-induced CKD. The animals were sacrificed 1 and 3 months after 5/6 Nx or sham operation. Nephrectomized rats presented higher concentrations of serum creatinine, urea nitrogen, and parathyroid hormone both 1 and 3 months after nephrectomy. These animals revealed higher concentrations of kynurenine and 3-hydroxykynurenine in the serum and higher gene expression of aryl hydrocarbon receptor (AhR) as a physiological receptor for kynurenine and AhR-dependent cytochrome in the bone tissue. Furthermore, nephrectomy significantly increased the number of osteoclasts in the bone without affecting their resorptive activity measured in serum. These changes were particularly evident in rats 1 month after 5/6 Nx. The main bone biomechanical parameters of the tibia were unchanged between nephrectomized and sham-operated rats but were significantly increased in older compared to younger animals. A similar trend was observed for geometrical parameters measured with calipers, bone mineral density based on Archimedes' method and image of bone microarchitecture obtained from micro-computed tomography analyses of tibial cortical bone. In nephrectomized animals, peripheral kynurenine levels correlated negatively with the main parameters of bone biomechanics, bone geometry, and bone mineral density values. In conclusion, our data suggest that CKD-induced elevated levels of peripheral kynurenine cause pathological changes in bone structure via AhR pathway. This finding opens new opportunities for the treatment/prevention of osteoporosis in CKD.

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“…Abnormalities in the tryptophan/serotonin/kynurenine pathway have also been implicated in the pathogenesis of the bone disease associated with chronic kidney disease (CKD-MBD) [ 70 , 71 ]. Kalaska et al [ 72 ] examined the correlation between serum kynurenine metabolites and parameters of bone turnover in rats after partial nephrectomy.…”

Section: Xanthurenic Acid Induces Cell Apoptosismentioning

confidence: 99%

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Anaya

Bollag

Hamrick

et al. 2020

IJMS

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Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.

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The Association between Elevated Levels of Peripheral Serotonin and Its Metabolite – 5-Hydroxyindoleacetic Acid and Bone Strength and Metabolism in Growing Rats with Mild Experimental Chronic Kidney Disease

Cited by 28 publications

References 57 publications

Improving results in rat fracture models: enhancing the efficacy of biomechanical testing by a modification of the experimental setup

Improving results in rat fracture models: enhancing the efficacy of biomechanical testing by a modification of the experimental setup

Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

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